The substitution of fluorine for chlorine or another halogen atom at an aromatic carbon of a tri- or tetrahalophthalimide is an integral reaction in the production of many widely used organic compounds. As such, it is a reaction of considerable commercial importance. For example, the conversion of N-methyltetrachlorophthalimide to N-methyltetrafluorophthalimide is an important step in the production of compounds in the Floxacin family of antibiotics, a commonly prescribed, commercially successful group of synthetic drugs.
A problem typically encountered with halogen-exchange fluorination is the propensity for the formation of products in which at least one aromatic carbon remains substituted by a non-fluorine halogen atom. For example, the halogen-exchange fluorination of a tetrachlorinated phthalimide substrate can lead to mono-, di- and trifluorinated products in addition to the tetrafluorinated product, often the desired end product of the reaction. This tendency towards incomplete halogen-exchange fluorination of halophthalimides generally has the effect of reducing the purity and yield of the fully-exchanged product. In particular, the fluorination of tetrachlorophthalimides, typically carried out with a metal fluoride salt in solvents such as sulfolane, often produces substantially only partially-exchanged products, especially when conducted at moderate temperatures such as those in the range of 150.degree. C.
In order to increase the proportion of the fully-exchanged phthalimide, the reaction is often run at temperatures in excess of 200.degree. C., and for durations of ten hours or more. Unfortunately, such high temperatures and long reaction times are often of limited effectiveness, as such conditions can ultimately result in degradation of the phthalimide moiety. In order to allow the use of conditions which are less harsh, it is typical to perform the reaction in the presence of a phase-transfer catalyst.
However, many phase-transfer catalysts can be extremely costly. It is not unusual for the small amount of phase-transfer catalyst utilized to cost more than any other chemical component of the reaction. A further disadvantage associated with these catalysts is that further processing of even residual amounts of phase-transfer catalyst can result in the formation of tarry impurities due to polymerization of the catalyst. Thus, once halogen-exchange fluorination has been conducted, it is often necessary to resort to purification techniques in order to separate the catalyst from the desired product.
A multiple extraction procedure is typically performed to accomplish this end. Unfortunately, extraction and other methods which can be used to remove the catalyst from the reaction mixture following halogen-exchange fluorination can reduce the yield of the desired product and complicate the reaction work-up. Another problem created by the addition of extraction steps to the synthesis is the increased difficulty in recycling solvents due to contamination with extractant reagents. Recycling can be particularly important if the solvent is costly, as in the case of one commonly used solvent, sulfolane. For example, in the event that sulfolane and water were used as solvent and extractant, respectively, the sulfolane would typically need to be dried before reuse.
It would represent a significant advance in the state of the art if a method of halogen-exchange fluorination of tri- and tetrahalophthalimides which contain non-fluorine halogens could be found which can achieve a high yield and rate of production of fully-exchanged product while eliminating the expense, multiple extractions, and solvent recycling problems associated with phase-transfer catalysts.